Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice
Permanent scars form upon healing of tissue injuries such as those caused by ischemia (myocardial infarction, stroke), trauma, surgery, and inflammation. Current options in reducing scar formation are limited to local intervention. We have designed a systemically administered, target-seeking biother...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2010-12, Vol.107 (50), p.21671-21676 |
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| creator | Järvinen, Tero A. H. Ruoslahti, Erkki |
| description | Permanent scars form upon healing of tissue injuries such as those caused by ischemia (myocardial infarction, stroke), trauma, surgery, and inflammation. Current options in reducing scar formation are limited to local intervention. We have designed a systemically administered, target-seeking biotherapeutic for scar prevention. It consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin. Decorin prevents tissue fibrosis and promotes tissue regeneration by inhibiting TGF-β activity and by other regulatory activities. The decorin-targeting peptide fusion protein had substantially increased neutralizing activity against TGF-β1 in vitro compared with untargeted decorin. In vivo, the fusion protein selectively accumulated in wounds, and promoted wound healing and suppressed scar formation at doses where nontargeted decorin was inactive. These results show that selective targeting yields a tissue-healing and scar-reducing compound with enhanced specificity and potency. This approach may help make reducing scar formation by systemic drug delivery a feasible option for surgery and for the treatment of pathological processes in which scar formation is a problem. |
| doi_str_mv | 10.1073/pnas.1016233107 |
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H. ; Ruoslahti, Erkki</creator><creatorcontrib>Järvinen, Tero A. H. ; Ruoslahti, Erkki</creatorcontrib><description>Permanent scars form upon healing of tissue injuries such as those caused by ischemia (myocardial infarction, stroke), trauma, surgery, and inflammation. Current options in reducing scar formation are limited to local intervention. We have designed a systemically administered, target-seeking biotherapeutic for scar prevention. It consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin. Decorin prevents tissue fibrosis and promotes tissue regeneration by inhibiting TGF-β activity and by other regulatory activities. The decorin-targeting peptide fusion protein had substantially increased neutralizing activity against TGF-β1 in vitro compared with untargeted decorin. In vivo, the fusion protein selectively accumulated in wounds, and promoted wound healing and suppressed scar formation at doses where nontargeted decorin was inactive. These results show that selective targeting yields a tissue-healing and scar-reducing compound with enhanced specificity and potency. This approach may help make reducing scar formation by systemic drug delivery a feasible option for surgery and for the treatment of pathological processes in which scar formation is a problem.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1016233107</identifier><identifier>PMID: 21106754</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Amino Acid Sequence ; Angiogenesis ; Animals ; Automobiles ; Biological Sciences ; Blood Vessels - metabolism ; CHO Cells ; Cicatrix - drug therapy ; Cicatrix - pathology ; Cricetinae ; Cricetulus ; Decorin - genetics ; Decorin - pharmacology ; Decorin - therapeutic use ; Fibroblasts ; Fibrosis - pathology ; Granulation tissue ; Homing ; Humans ; Mice ; Molecular Sequence Data ; Molecules ; Neovascularization, Physiologic ; Pathology ; Peptides ; Peptides - genetics ; Peptides - pharmacology ; Peptides - therapeutic use ; Physical trauma ; Proteins ; Proteoglycans ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - pharmacology ; Recombinant Fusion Proteins - therapeutic use ; Rodents ; Scars ; Skin ; Transforming Growth Factor beta1 - metabolism ; Wound healing ; Wound Healing - drug effects</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2010-12, Vol.107 (50), p.21671-21676</ispartof><rights>Copyright National Academy of Sciences Dec 14, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c532t-89b7be8209bda59e62397c451d4fdb108034d6af28eac20a5eea7c647cc50a583</citedby><cites>FETCH-LOGICAL-c532t-89b7be8209bda59e62397c451d4fdb108034d6af28eac20a5eea7c647cc50a583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/107/50.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25756942$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25756942$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,724,777,781,800,882,27905,27906,53772,53774,57998,58231</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21106754$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Järvinen, Tero A. H.</creatorcontrib><creatorcontrib>Ruoslahti, Erkki</creatorcontrib><title>Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Permanent scars form upon healing of tissue injuries such as those caused by ischemia (myocardial infarction, stroke), trauma, surgery, and inflammation. Current options in reducing scar formation are limited to local intervention. We have designed a systemically administered, target-seeking biotherapeutic for scar prevention. It consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin. Decorin prevents tissue fibrosis and promotes tissue regeneration by inhibiting TGF-β activity and by other regulatory activities. The decorin-targeting peptide fusion protein had substantially increased neutralizing activity against TGF-β1 in vitro compared with untargeted decorin. In vivo, the fusion protein selectively accumulated in wounds, and promoted wound healing and suppressed scar formation at doses where nontargeted decorin was inactive. These results show that selective targeting yields a tissue-healing and scar-reducing compound with enhanced specificity and potency. This approach may help make reducing scar formation by systemic drug delivery a feasible option for surgery and for the treatment of pathological processes in which scar formation is a problem.</description><subject>Amino Acid Sequence</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Automobiles</subject><subject>Biological Sciences</subject><subject>Blood Vessels - metabolism</subject><subject>CHO Cells</subject><subject>Cicatrix - drug therapy</subject><subject>Cicatrix - pathology</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Decorin - genetics</subject><subject>Decorin - pharmacology</subject><subject>Decorin - therapeutic use</subject><subject>Fibroblasts</subject><subject>Fibrosis - pathology</subject><subject>Granulation tissue</subject><subject>Homing</subject><subject>Humans</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Molecules</subject><subject>Neovascularization, Physiologic</subject><subject>Pathology</subject><subject>Peptides</subject><subject>Peptides - genetics</subject><subject>Peptides - pharmacology</subject><subject>Peptides - therapeutic use</subject><subject>Physical trauma</subject><subject>Proteins</subject><subject>Proteoglycans</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - pharmacology</subject><subject>Recombinant Fusion Proteins - therapeutic use</subject><subject>Rodents</subject><subject>Scars</subject><subject>Skin</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><subject>Wound healing</subject><subject>Wound Healing - drug effects</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc2PFCEQxYnRuOPq2ZOGePHUbkFDQ19MzMavZBMv65nQdPUMYze00L3G_17GGXfUExT1qxdePUKeM3jDQNVXc7C53FjD67o8PCAbBi2rGtHCQ7IB4KrSgosL8iTnPQC0UsNjcsEZg0ZJsSH21qYtLlVG_ObDltqw-MF3KS7eURenOa6hpxh2NjjM9Mfvcod2PMI9zes8J8y5NLOziQ4xTXbxMVAf6OQdPiWPBjtmfHY6L8nXD-9vrz9VN18-fr5-d1M5WfOl0m2nOtQc2q63ssXiqFVOSNaLoe8YaKhF39iBa7SOg5WIVrlGKOdkqXR9Sd4edee1m7B3GJZkRzMnP9n000Trzb-d4HdmG-9MDVB2J4vA65NAit9XzIuZfHY4jjZgXLPRUnMtoKkL-eo_ch_XFIo7o5mWZfnyAF0dIZdizgmH-68wMIfwzCE8cw6vTLz828E9_yetAtATcJg8yykjoVCNYgV5cUT2eYnpLCGVbFrB619z86v7</recordid><startdate>20101214</startdate><enddate>20101214</enddate><creator>Järvinen, Tero A. H.</creator><creator>Ruoslahti, Erkki</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20101214</creationdate><title>Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice</title><author>Järvinen, Tero A. H. ; Ruoslahti, Erkki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c532t-89b7be8209bda59e62397c451d4fdb108034d6af28eac20a5eea7c647cc50a583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Amino Acid Sequence</topic><topic>Angiogenesis</topic><topic>Animals</topic><topic>Automobiles</topic><topic>Biological Sciences</topic><topic>Blood Vessels - metabolism</topic><topic>CHO Cells</topic><topic>Cicatrix - drug therapy</topic><topic>Cicatrix - pathology</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Decorin - genetics</topic><topic>Decorin - pharmacology</topic><topic>Decorin - therapeutic use</topic><topic>Fibroblasts</topic><topic>Fibrosis - pathology</topic><topic>Granulation tissue</topic><topic>Homing</topic><topic>Humans</topic><topic>Mice</topic><topic>Molecular Sequence Data</topic><topic>Molecules</topic><topic>Neovascularization, Physiologic</topic><topic>Pathology</topic><topic>Peptides</topic><topic>Peptides - genetics</topic><topic>Peptides - pharmacology</topic><topic>Peptides - therapeutic use</topic><topic>Physical trauma</topic><topic>Proteins</topic><topic>Proteoglycans</topic><topic>Recombinant Fusion Proteins - genetics</topic><topic>Recombinant Fusion Proteins - pharmacology</topic><topic>Recombinant Fusion Proteins - therapeutic use</topic><topic>Rodents</topic><topic>Scars</topic><topic>Skin</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><topic>Wound healing</topic><topic>Wound Healing - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Järvinen, Tero A. 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H.</au><au>Ruoslahti, Erkki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2010-12-14</date><risdate>2010</risdate><volume>107</volume><issue>50</issue><spage>21671</spage><epage>21676</epage><pages>21671-21676</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Permanent scars form upon healing of tissue injuries such as those caused by ischemia (myocardial infarction, stroke), trauma, surgery, and inflammation. Current options in reducing scar formation are limited to local intervention. We have designed a systemically administered, target-seeking biotherapeutic for scar prevention. It consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin. Decorin prevents tissue fibrosis and promotes tissue regeneration by inhibiting TGF-β activity and by other regulatory activities. The decorin-targeting peptide fusion protein had substantially increased neutralizing activity against TGF-β1 in vitro compared with untargeted decorin. In vivo, the fusion protein selectively accumulated in wounds, and promoted wound healing and suppressed scar formation at doses where nontargeted decorin was inactive. These results show that selective targeting yields a tissue-healing and scar-reducing compound with enhanced specificity and potency. This approach may help make reducing scar formation by systemic drug delivery a feasible option for surgery and for the treatment of pathological processes in which scar formation is a problem.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21106754</pmid><doi>10.1073/pnas.1016233107</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Angiogenesis Animals Automobiles Biological Sciences Blood Vessels - metabolism CHO Cells Cicatrix - drug therapy Cicatrix - pathology Cricetinae Cricetulus Decorin - genetics Decorin - pharmacology Decorin - therapeutic use Fibroblasts Fibrosis - pathology Granulation tissue Homing Humans Mice Molecular Sequence Data Molecules Neovascularization, Physiologic Pathology Peptides Peptides - genetics Peptides - pharmacology Peptides - therapeutic use Physical trauma Proteins Proteoglycans Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - pharmacology Recombinant Fusion Proteins - therapeutic use Rodents Scars Skin Transforming Growth Factor beta1 - metabolism Wound healing Wound Healing - drug effects |
| title | Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice |
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